This invention relates to radioiodinated compounds which are useful as radiopharmaceuticals and biological probes, and more specifically, to radioiodinated phospholipid analogues of the naturally-occurring ether, alkyl lysophospholipid, and alkyl phosphocholine which are tumor-specific and can be used for gamma-camera scintigraphy.
Currently, most scintigraphic procedures for tumor-imaging utilize organ-specific radiodiagnostics which rely upon alteration of the radioactivity distribution within normal tissue for external visualization of tumors. The variations may appear as either an area of increased, or decreased, radioactivity within the tissue. A problem which has been encountered with these known radiodiagnostics is that many biological conditions, such as abscesses or other inflammations, can cause a disturbance in the radioactivity distribution pattern.
There are presently not available radiopharmaceuticals which will specifically image neoplastic lesions by non-invasive nuclear medicine techniques. The current radiodiagnostic agent of choice for scintigraphy, gallium-67 citrate, will localize, or accumulate, in a tumor causing it to appear as an area of increased radioactivity when examined externally via a gamma camera. However, gallium-67 citrate is not tumor-specific (defined herein as localizing only in tumors) since it also accumulates in a variety of other inflammatory lesions. In addition, normal liver and spleen tissue typically exhibit high concentrations of radioactivity with the use of gallium-67 citrate. As a result, it is difficult to identify abnormal accumulations of radioactivity in or adjacent to these tissues. An additional disadvantage of gallium-67 citrate is that the distribution of this agent can be altered by a variety of steroidal and antineoplastic drugs. Thus, the usefulness of gallium-67 citrate is limited after chemotherapy has been initiated.
Other tumor-localizing agents such as selenomethionine [.sup.75 Se] and bleomycin labelled with .sup.111 In, .sup.57 Co, or .sup.99 Tc, have been investigated. However, these agents are not tumor-specific, nor have they exhibited any obvious advantages over gallium-67 citrate.
Monoclonal antibodies have been developed which are tumor-specific. However, monoclonal antibodies are specific only to the particular tumor tissue for which they have been produced and will not localize generally in neoplastic tissue. Moreover, the use of monoclonal antibodies can result in adverse immunogenic reactions.
There is, therefore, a need in the art for a radiopharmaceutical which is tumor-specific to neoplastic tissue, and not merely tumor-localizing. Such an agent would not only provide a non-invasive technique for the detection of primary tumors and metastases but would enable monitoring of tumor reduction during therapy.
Some analogues of the naturally-occurring lipid ether, alkyl lysophospholipid, have exhibited an antitumor activity. ##STR3## The mechanism which underlies this activity is not entirely understood. However, a direct cytotoxic action appears to be involved.
Referring to FIG. 13, a schematic representation of the phospholipid ether catabolic pathway is illustrated. The normal cellular degradation of the ether phospholipid, 1-alkyl-2-acyl-sn-glycero-3-phosphocholine involves deacylation by phospholipase A.sub.2 in the 2-position to yield alkyl lysophospholipid. This is followed by the cleavage of the ether bond by the 1-0-alkyl cleavage enzyme to afford sn-glycero-3-phosphocholine. An alternative degradative pathway of alkyl lysophospholipid involves the removal of the phosphocholine moiety. This occurs by the sequential actions of lysophospholipase D and a phosphohydrolase and yields a metabolite of alkyl lysophospholipid, 1-O-alkyl glycerol. Further degradation of this alkyl glycerol requires the 1-O-alkyl cleavage enzyme.
It is proposed that the alkyl lysophospholipid analogues accumulate in tumor cells, thus altering the natural phospholipid metabolism, and are cytotoxic, resulting in cell death. This accumulation is partially attributed to a decrease in activity of the 1-O-alkyl cleavage enzyme which is responsible for cleavage of the ether bond. Reduction in the enzyme's activity retards degradation of the lipids and results in an accumulation of endogenous ether lipids in the tumors. It would be advantageous to develop analogues of the naturally-occurring alkyl lysophospholipid which can be rendered radioactive, will be stable once radiolabelled, and will accumulate specifically in neoplastic tumor tissue.
It is, therefore, an object of this invention to provide a radiopharmaceutical for gamma camera scintigraphy.
It is another object of this invention to provide a radiopharmaceutical for selective visualization of neoplastic lesions.
It is also an object of this invention to provide a radiopharmaceutical which represents an improvement over currently available agents, such as gallium-67 citrate, in that it is tumor-specific versus tumor-localizing.
It is a further object of this invention to provide a radiopharmaceutical such that its radioactivity distribution will not be altered by the action of other drugs, such as steroids and antineoplasts, and therefore can be used to monitor tumor reduction during therapy.
It is additionally an object of this invention to provide a non-invasive technique for detection of primary tumors and metastases.
It is yet a further object of this invention to provide a radiolabelled compound which is similar to platelet activating factor and can be used as a biological probe to study the metabolism of platelet activating factor.
It is also another object of this invention to provide a radiopharmaceutical which is selective to neoplastic tissue, but which is non-specific as to type of neoplastic tissue as are prior art monoclonal antibodies.
It is yet an additional object of this invention to provide a radiopharmaceutical which is non-immunogenic.
It is still another object of this invention to provide a radiopharmaceutical which is not complex in structure and is easily and inexpensively synthesized.
It is a yet further object of this invention to provide a radiopharmaceutical which is cytotoxic for therapeutic purposes.
It is still a further object of this invention to provide a radiopharmaceutical which is useful for radiotherapy.